α, α dialkylbenzyl derivatives

ABSTRACT

The invention concerns α,α-dialkylbenzyl derivatives of the formula I ##STR1## wherein Ar 1  is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur; 
     A 1  is a direct link to X 1  or is (1-3C)alkylene; 
     X 1  is oxy, thio, sulphinyl or sulphonyl; 
     the phenylene group may optionally bear one or two substituents R 3  ; 
     each of R 1  and R 2 , which may be the same or different is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, fluoro-(1-4C)alkyl, phenyl or phenyl-(1-4C)alkyl, provided that both of R 1  and R 2  are not methyl or fluoromethyl; and 
     Q is cyano, amino, nitro, formyl, (1-4C)alkoxy, thiazolyl or (2-4C)alkanoyl; 
     or a pharmaceutically-acceptable salt thereof; 
     processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

This is a continuation of application Ser. No. 07/853,277, filed Mar.18, 1992 now U.S. Pat. No. 5,288,742.

This invention concerns α,α-dialkylbenzyl derivatives and moreparticularly α,α-dialkylbenzyl derivatives which are inhibitors of theenzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The inventionalso concerns processes for the manufacture of said α,α-dialkylbenzylderivatives and pharmaceutical compositions containing them. Alsoincluded in the invention is the use of said α,α-dialkylbenzylderivatives in the treatment of various inflammatory and/or allergicdiseases in which the direct or indirect products of 5-LO catalysedoxidation of arachidonic acid are involved, and the production of newmedicaments for such use.

As stated above the α,α-dialkylbenzyl derivatives described hereinafterare inhibitors of 5-LO, which enzyme is known to be involved incatalysing the oxidation of arachidonic acid to give rise via a cascadeprocess to the physiologically active leukotrienes such as leukotrieneB₄ (LTB₄) and the peptido-lipid leukotrienes such as leukotriene C₄(LTC₄) and leukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trendsin Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes andtheir metabolites have been implicated in the production and developmentof various inflammatory and allergic diseases such as inflammation ofthe joints (especially rheumatoid arthritis, oesteoarthritis and gout),inflammation of the gastrointestinal tract (especially inflammatorybowel disease, ulcerative colitis and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis and allergic rhinitis), and in theproduction and development of various cardiovascular and cerebrovasculardisorders such as myocardial infarction, angina and peripheral vasculardisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolites of arachidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

It is known from European Patent Application No. 0181568 that3-(quinolin-2-ylmethoxy)phenylacetic acid and2-[3-(quinolin-2-ylmethoxy)phenyl]propionic acid and certain methyl orethyl esters thereof possess anti-inflammatory properties.

It is also disclosed in European Patent Application No. 0414076 thatfurther 4-(quinolin-2-ylmethoxy)phenylacetic acid derivatives areinhibitors of the enzyme lipoxygenase.

We have now discovered that the acid group is not mandatory and may bereplaced by several other groups.

Thus we have now discovered that certain α,α-dialkylbenzyl derivativesare effective as inhibitors of the enzyme 5-LO and thus of leukotrienebiosyntheses. Thus, such compounds are of value as therapeutic agents inthe treatment of, for example, allergic conditions, psoriasis, asthma,cardiovascular and cerebrovascular disorders, and/or inflammatory andarthritic conditions, mediated alone or in part by one or moreleukotrienes.

According to the invention there is provided an α,α-dialkylbenzylderivative of the formula I (set out hereinafter) wherein Ar¹ is phenylor naphthyl, or a 10-membered bicyclic heterocyclic moiety containingone or two nitrogen heteroatoms and optionally containing a furtherheteroatom selected from nitrogen, oxygen and sulphur, and Ar¹ mayoptionally bear up to four substituents selected from halogeno, hydroxy,cyano, oxo, thioxo, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl,phenyl, benzoyl, phenyl-(1-4C)alkyl, α,α-difluorobenzyl, α-hydroxybenzyland α-[(1-4C)alkoxy]benzyl and wherein said phenyl substituent or any ofsaid substituents which contain a phenyl group may optionally bear asubstituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;

A¹ is a direct link to X¹ or is (1-3C)alkylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

the phenylene group may optionally bear one or two substituents R³selected from halogeno, hydroxy, amino, nitro, cyano, carbamoyl, ureido,(1-4C)alkyl, (1-4C)alkoxy and fluoro-(1-4C)alkyl;

each of R¹ and R², which may be the same or different, is (1-4C)alkyl(2-4C)alkenyl, (2-4C)alkynyl, fluoro-(1-4C)alkyl, phenyl orphenyl-(1-4C)alkyl and wherein said phenyl or phenyl-(1-4C)alkyl groupmay optionally bear one or two substituents selected from halogeno,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, provided that both of R¹and R² are not methyl or fluoromethyl; and

Q is cyano, amino, nitro, formyl, (1-4C)alkoxy, thiazolyl or(2-4C)alkanoyl;

or a pharmaceutically-acceptable salt thereof.

According to a further aspect of the invention there is provided anα,α-dialkylbenzyl derivative of the formula I wherein Ar¹ is phenyl ornaphthyl, or a 10-membered bicyclic heterocyclic moiety containing oneor two nitrogen heteroatoms and optionally containing a furtherheteroatom selected from nitrogen, oxygen and sulphur, and Ar¹ mayoptionally bear up to four substituents selected from halogeno, hydroxy,cyano, oxo, thioxo, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl,phenyl, benzoyl, phenyl-(1-4C)alkyl, α,α-difluorobenzyl, α-hydroxybenzyland α-[(1-4C)alkoxy]benzyl and wherein said phenyl substituent or any ofsaid substituents which contain a phenyl group may optionally bear asubstituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;

A¹ is a direct link to X¹ or is (1-3C)alkylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

the phenylene group may optionally bear one or two substituents R³selected from halogeno, hydroxy, amino, nitro, cyano, carbamoyl, ureido,(1-4C)alkyl, (1-4C)alkoxy and fluoro-(1-4C)alkyl;

each of R¹ and R², which may be the same or different is (2-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl or fluoro-(2-4C)alkyl; and

Q is cyano, amino, nitro, formyl, (1-4C)alkoxy or thiazolyl;

or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as "propyl" are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as "isopropyl" are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of theformula I defined above may exhibit the phenomenon of tautomerism andany formula drawing presented herein may represent only one of thepossible tautomeric forms, the invention includes in its definition anytautomeric form of a compound of the formula I which possesses theproperty of inhibiting 5-LO and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

It is further to be understood that, insofar as certain of the compoundsof formula I defined above may exist in optically active or racemicforms by virtue of one or more substituents containing an asymmetriccarbon atom, the invention includes in its definition any such opticallyactive or racemic form which possesses the property of inhibiting 5-LO.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against 5-LO may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic terms referred to above include thoseset out below.

A suitable value for Ar¹ when it is naphthyl is, for example 1-naphthylor 2-naphthyl.

A suitable value for Ar¹ when it is a 10-membered bicyclic heterocyclicmoiety containing one or two nitrogen heteroatoms and optionallycontaining a further heteroatom selected from nitrogen, oxygen andsulphur is, for example, a 10-membered benzo-fused heterocyclic moietysuch as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,4H-1,4-benzoxazinyl or 4H-1,4-benzothiazinyl, or a hydrogenatedderivative thereof such as 1,2-dihydroquinolyl,1,2,3,4-tetrahydroquinolyl, 1,2-dihydroisoquinolyl,2,3-dihydro-4H-1,4-benzoxazinyl or 2,3-dihydro-4H-1,4-benzothiazinyl;or, for example, a 10-membered pyrido-fused heterocyclic moiety such as1,7-naphthyridinyl, 1,8-naphthyridinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-b]pyrazinyl, 4H-pyrido[3,2-b][1,4]oxazinyl and4H-pyrido[3,2-b][1,4]thiazinyl, or a hydrogenated derivative thereof.

The heterocyclic moiety may be attached through any available positionincluding from either of the two rings of the bicyclic heterocyclicmoiety and including through an available nitrogen atom. Theheterocyclic moiety may bear a suitable substituent such as, forexample, a (1-4C)alkyl, phenyl, benzoyl or phenyl-(1-4C)alkylsubstituent on an available nitrogen atom.

Suitable values for substituents which may be present on Ar¹, on thephenylene group, on the phenyl substituent on Ar¹ or on any of thesubstituents on Ar¹ which contain a phenyl group or on R¹ or R² wheneach is phenyl or phenyl-(1-4C)alkyl, include, for example:

for halogeno: fluoro, chloro, bromo and iodo;

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl;

for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for fluoro-(1-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;

for phenyl-(1-4C)alkyl: benzyl, phenethyl, 3-phenylpropyl andα-methylbenzyl;

for α-[(1-4C)alkoxy]benzyl: α-methoxybenzyl and α-ethoxybenzyl.

A suitable value for A¹ when it is (1-3C)alkylene is, for example,methylene, ethylene or trimethylene.

A suitable value for the phenylene group is, for example, 1,3-phenyleneor 1,4-phenylene.

A suitable value for R¹ or R² when it is (1-4C)alkyl is, for example,methyl, ethyl, propyl, isopropyl or butyl; when it is (2-4C)alkenyl is,for example, vinyl of allyl; when it is (2-4C)alkynyl is, for example,ethynyl or 2-propynyl; when it is fluoro-(1-4C)alkyl is, for example,fluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl;and when it is phenyl-(1-4C)alkyl is, for example, benzyl or phenethyl.

A suitable value for Q when it is (1-4C)alkoxy is, for example, methoxy,ethoxy or propoxy; when it is thiazolyl is, for example, 2-, 4- or5-thiazolyl; and when it is (2-4C)alkanoyl is, for example, acetyl,propionyl or butyryl.

A suitable pharmaceutically-acceptable salt of a novel compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a novel compound of the inventionwhich is sufficiently acidic is an alkali metal salt, for example asodium or potassium salt, an alkaline earth metal salt, for example acalcium or magnesium salt, an ammonium salt or a salt with an organicbase which affords a physiologically-acceptable cation, for example asalt with methylamine, dimethylamine, trimethylamine, piperidine,morpholine or tris-(2-hydroxyethyl)amine.

Particular compounds of the invention are, for example,α,α-dialkylbenzyl derivatives of the formula I wherein:

(a) Ar¹ is phenyl or naphthyl which may optionally bear one, two orthree substituents selected from any of those substituents on Ar¹defined hereinbefore other than oxo and thioxo; and A¹, X¹, R¹, R², R³,and Q have any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention;

(b) Ar¹ is phenyl or naphth-2-yl which may optionally bear one or twosubstituents selected from fluoro, chloro, methyl, ethyl, isopropyl,tert-butyl, methoxy, trifluoromethyl, phenyl, benzoyl, benzyl,α,α-difluorobenzyl and α-methoxybenzyl, and wherein said phenyl,benzoyl, benzyl, α,α-difluorobenzyl or α-methoxybenzyl substituents mayoptionally bear a substituent selected from fluoro, chloro, methyl andmethoxy; and A¹, X¹, R¹, R², R³ and Q have any of the meanings definedhereinbefore or in this section concerning particular compounds of theinvention;

(c) Ar¹ is a 10-membered benzo-fused heterocyclic moiety containing oneor two nitrogen heteroatoms and optionally containing a furtherheteroatom selected from oxygen and sulphur, which heterocyclic moietymay optionally bear one or two oxo or thioxo substituents and up to twofurther substituents selected from any of those substituents on Ar¹defined hereinbefore other than oxo or thioxo; and A¹, X¹, R¹, R², R³and Q have any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention;

(d) Ar¹ is quinolyl, 1,2-dihydroquinolyl, isoquinolyl,1,2-dihydroisoquinolyl, quinoxalinyl, 2,3-dihydro-4H-1,4-benzoxazinyl or2,3-dihydro-4H-1,4-benzothiazinyl, which may optionally bear one or twooxo or thioxo substituents and up to two further substituents selectedfrom any of those substituents on Ar¹ defined hereinbefore other thanoxo or thioxo; and A¹, X¹, R¹, R², R³ and Q have any of the meaningsdefined hereinbefore or in this section concerning particular compoundsof the invention;

(e) Ar¹ is quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl or2,3-dihydro-4H-1,4-benzoxazinyl which may optionally bear one oxo orthioxo substituent and up to two further substituents selected from anyof those substituents on Ar¹ defined hereinbefore other than oxo orthioxo; and A¹, X¹, R¹, R², R³ and Q have any of the meanings definedhereinbefore or in this section concerning particular compounds of theinvention;

(f) Ar¹ is 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl,3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 2-quinoxalinyl,6-quinoxalinyl, 4H-1,4-benzoxazin-6-yl or 4H-1,4-benzothiazin-6-yl,which may optionally bear one or two substituents selected from any ofthose substituents on Ar¹ defined hereinbefore other than oxo or thioxo;and A¹, X¹, R¹, R², R³ and Q have any of the meanings definedhereinbefore or in this section concerning particular compounds of theinvention;

(g) Ar¹ is 2-oxo-1,2-dihydroquinolinyl,3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl or3-oxo-2,3-dihydro-4H-1,4-benzothiazinyl, or the corresponding thioxoderivatives thereof, which may optionally bear up to three substituentsselected from any of those substituents on Ar¹ defined hereinbeforeother than oxo or thioxo; and A¹, X¹, R¹, R², R³ and Q have any of themeanings defined hereinbefore or in this section concerning particularcompounds of the invention;

(h) Ar¹ is 2-oxo-1,2-dihydroquinolinyl, 2-thioxo-1,2-dihydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl,2-thioxo-1,2,3,4-tetrahydroquinolinyl or3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl which may optionally bear up tothree substituents selected from any of those substituents on Ar¹defined hereinbefore other than oxo or thioxo; and A¹, X¹, R¹, R², R³and Q have any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention;

(i) Ar¹ is 2-oxo-1,2-dihydroquinolin-3-yl,2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl,3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, which may optionally bear upto three substituents selected from any of those substituents on Ar¹defined hereinbefore other than oxo or thioxo; and A¹, X¹, R¹, R², R³and Q have any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention;

(j) Ar¹ is a direct link to X¹, and X¹ is oxy, thio, sulphinyl orsulphonyl; and Ar¹, R¹, R², R³ and Q have any of the meanings definedhereinbefore or in this section concerning particular compounds of theinvention;

(k) A¹ is methylene and X¹ is oxy, thio, sulphinyl or sulphonyl; andAr¹, R¹, R², R³ and Q have any of the meanings defined hereinbefore orin this section concerning particular compounds of the invention;

(l) the phenylene group is 1,3-phenylene which may optionally bear oneor two substituents R³ selected from fluoro, chloro, hydroxy, amino,nitro, ureido methyl methoxy and trifluoromethyl; and Ar¹, A¹, X¹, R¹,R² and Q have any of the meanings defined hereinbefore or in thissection concerning particular compounds of the invention;

(m) each of R¹ and R², which may be the same or different is ethylpropyl, allyl, 2-fluoroethyl or 2 2,2-trifluoroethyl; and Ar¹, A¹, X¹,R³ and Q have any of the meanings defined hereinbefore or in thissection concerning particular compounds of the invention;

(n) each of R¹ and R², which may be the same or different is methyl,ethyl, propyl, allyl, fluoromethyl, 2-fluoroethyl or benzyl and whereinsaid benzyl group may optionally bear one or two substituents selectedfrom fluoro, chloro and trifluoromethyl, provided that both of R¹ and R²are not methyl or fluoromethyl; and Ar¹, A¹, X¹, R³ and Q have any ofthe meanings defined hereinbefore or in this section concerningparticular compounds of the invention;

(o) Q is cyano, amino, formyl, methoxy, ethoxy or 2-thiazolyl and Ar¹,A¹, X¹, R¹, R² and R³ have any of the meanings defined hereinbefore orin this section concerning particular compounds of the invention;

(p) Q is cyano, amino, formyl, methoxy, ethoxy, propoxy, 2-thiazolyl,acetyl or propionyl; and Ar¹, A¹, X¹, R¹, R² and R³ have any of themeanings defined hereinbefore or this section concerning particularcompounds of the invention;

(q) Q is cyano, acetyl or propionyl; and Ar¹, A¹, X¹, R¹, R² and R³ haveany of the meanings defined hereinbefore or in this section concerningparticular compounds of the invention;

(r) Q is methoxy, ethoxy or propoxy; and Ar¹, A¹, X¹, R¹, R² and R³ haveany of the meanings defined hereinbefore or in this section concerningparticular compounds of the invention; and

(s) Q is 2-thiazolyl; and Ar¹, A¹, X¹, R¹, R² and R³ have any of themeanings defined hereinbefore or in this section concerning particularcompounds of the invention.

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises an α,α-dialkylbenzylderivative of the formula I wherein Ar¹ is phenyl which may optionallybear a substituent selected from fluoro, chloro, methyl, tert-butyl,phenyl, benzoyl, benzyl and α,α-difluorobenzyl and wherein said phenyl,benzoyl, benzyl or α,α-difluorobenzyl substituent may optionally bear afluoro or chloro substituent, or Ar¹ is naphth-2-yl which may optionallybear a substituent selected from fluoro, chloro and methyl;

A¹ is a direct link to X¹, or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

the phenylene group is 1,3-phenylene which may optionally bear onesubstituent R³ selected from fluoro, chloro and trifluoromethyl;

each of R¹ and R², which may be the same or different is methyl, ethylpropyl allyl or benzyl provided that both of R¹ and R² are not methyl;and

Q is cyano, methoxy, ethoxy, 2-thiazolyl, acetyl or propionyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I wherein Ar¹ is 2-quinolyl,6-quinolyl, 6-quinoxazinyl, 2-oxo-1,2-dihydroquinolin-3-yl,2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl,3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, which may optionally bearone, two or three substituents selected from fluoro, chloro, methyl,ethyl, 2-fluoroethyl, phenyl and benzyl;

A¹ is a direct link to X¹, or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

the phenylene group is 1,3-phenylene which may optionally bear onesubstituent R³ selected from fluoro, chloro and trifluoromethyl;

each of R¹ and R², which may be the same or different is methyl, ethyl,propyl, allyl or benzyl, provided that both of R¹ and R² are not methyl;and

Q is cyano, methoxy, ethoxy, 2-thiazolyl, acetyl or propionyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I wherein Ar¹ isnaphth-2-yl, 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl,1-methyl-2-thioxo-1,2-dihydroquinolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl;

A¹ is a direct link to X¹ and X¹ is thio, or A¹ is methylene and X¹ isoxy;

the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene;

each of R¹ and R² is ethyl; and

Q is cyano;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I wherein Ar¹ isnaphth-2-yl, 2-quinolyl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;

A¹ is methylene and X¹ is oxy:

the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene;

R¹ is ethyl or allyl;

R² is methyl, ethyl, allyl or benzyl; and

Q is cyano, methoxy, ethoxy, 2-thiazolyl or acetyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I

wherein Ar¹ is naphth-2-yl, 2-quinolyl or1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;

A¹ is methylene and X¹ is oxy;

the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene;

R¹ is ethyl or allyl;

R² is methyl, ethyl, allyl or benzyl; and

Q is cyano or acetyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I

wherein Ar¹ is naphth-2-yl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;

A¹ is methylene and X¹ is oxy;

the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene;

R¹ is ethyl or allyl;

R² is methyl, ethyl or allyl; and

Q is methoxy or ethoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises anα,α-dialkylbenzyl derivative of the formula I

wherein Ar¹ is naphth-2-yl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;

A¹ is methylene and X¹ is oxy;

the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene;

R¹ is ethyl or allyl;

R² is methyl, ethyl or allyl; and

Q is 2-thiazolyl;

or a pharmaceutically-acceptable salt thereof.

A specific especially preferred compound of the invention is thefollowing compound of The formula I, or a pharmaceutically-acceptablesalt thereof:

2-ethyl-2-[3-(naphth-2-ylmethoxy)phenyl]butyronitrile,

2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrile,

2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrile,

2,2-diallyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]acetonitrileor

3-ethyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pentan-2-one.

A compound of the invention comprising an α,α-dialkylbenzyl derivativeof the formula I, or a pharmaceutically-acceptable salt thereof, may beprepared by any process known to be applicable to the preparation ofstructurally-related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which, unless otherwise stated, Ar¹, A¹, X¹,R¹, R², R³ and Q have any of the meanings defined hereinbefore.

(a) The coupling, preferably in the presence of a suitable base, of acompound of the formula Ar¹ -A¹ -X¹ -H with a compound of the formula IIwherein Z is a displaceable group; provided that, when there is an aminoor hydroxy group in Ar¹ or on the phenylene group, or when Q is amino,any amino or hydroxy group may be protected by a conventional protectinggroup or alternatively any such group need not be protected, whereafterany undesired protecting group in Ar¹, the phenylene group or Q isremoved by conventional means.

A suitable displaceable group Z is, for example, a halogeno orsulphonyloxy group, for example a fluoro, chloro, bromo, iodo,methanesulphonyloxy or toluene-R-sulphonyloxy group.

A suitable base for The coupling reaction is, for example, an alkali oralkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride,for example sodium carbonate, potassium carbonate, sodium ethoxide,potassium butoxide, sodium hydroxide, potassium hydroxide, sodiumhydride or potassium hydride; or an organometallic base such as(1-4C)alkyl-lithium, for example n-butyl-lithium. The coupling reactionis conveniently performed in a suitable inert solvent or diluent, forexample N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone,1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in therange, for example, 10° to 150° C., conveniently at or near 100° C.

Conveniently the reaction may be performed in the presence of a suitablecatalyst, for example a metallic catalyst, for example palladium(O) orcopper(I) such as tetrakis(triphenylphosphine)palladium, cuprouschloride or cuprous bromide.

A suitable protecting group for an amino group is, for example, an acylgroup for example a (2-4C)alkanoyl group (especially acetyl), a(1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonylor tert-butoxycarbonyl), an arylmethoxycarbonyl group (especiallybenzyloxycarbonyl) or an aroyl group (especially benzoyl). Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl or an aroyl group may be removedfor example, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anacyl group such as a tert-butoxycarbonyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example a (2-4C)alkanoyl group (especially acetyl), an aroylgroup (especially benzoyl) or an arylmethyl group (especially benzyl).The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

The preparation of starting materials of the formula Ar¹ -A¹ -X¹ -H andof the formula II may be obtained by standard procedures of organicchemistry as illustrated in European Patent Applications Nos. 0375404,0385662, 0409413 and 0420511.

(b) The coupling of a compound of the formula Ar¹ -A¹ -X¹ -Z wherein Zis a displaceable group as defined hereinbefore, or alternatively, whenX¹ is a thio group, Z may be a group of the formula Ar¹ -A¹ -X¹ -, withan organometallic reagent of the formula III wherein M is an alkalimetal or an alkaline earth metal such as lithium or calcium or Mrepresents the magnesium halide portion of a conventional Grignardreagent; provided that, when there is an amino or hydroxy group in Ar¹or on the phenylene group, or when Q is amino, any amino or hydroxygroup may be protected by a conventional protecting group as definedhereinbefore or alternatively any such group need not be protected,whereafter any undesired protecting group in Ar¹, the phenylene group orQ is removed by conventional means.

The coupling reaction is conveniently performed in a suitable inertsolvent as defined hereinbefore and at a temperature in the range, forexample, -80° to +50° C., conveniently in the range -80° C. to ambienttemperature.

The preparation of starting materials of the formula Ar¹ -A¹ -X¹ -Z andof the formula III may be obtained by standard procedures of organicchemistry as illustrated in European Patent Applications Nos. 0375405,0385662, 0409413 and 0420511.

(c) The coupling, preferably in the presence of a suitable base asdefined hereinbefore, of a compound of the formula IV with a compound ofthe formula Ar¹ -A¹ -Z wherein Z is a displaceable group as definedhereinbefore; provided that, when there is an amino or hydroxy group inAr¹ or on the phenylene group, or when Q is amino, any amino or hydroxygroup may be protected by a conventional protecting group as definedhereinbefore or alternatively any such group need not be protected,whereafter any undesired protecting group in Ar¹, the phenylene group orQ is removed by conventional means.

The coupling reaction is conveniently performed in a suitable inertsolvent as defined hereinbefore and at a temperature in the range, forexample, 10° to 150° C., conveniently at or near 100° C. The reactionmay conveniently be performed in the presence of a suitable catalyst asdefined hereinbefore.

The starting materials of the formula Ar¹ -A¹ -Z and of the formula IVmay be obtained by standard procedures of organic chemistry asillustrated in European Patent Applications Nos. 0375405, 0385662,0409413 and 0420511. Starting materials of the formula IV are obtainableby analogous procedures to those illustrated in the accompanyingExamples or by modifications thereto which are within the ordinary skillof an organic chemist.

(d) For the production of those compounds of the formula I wherein Q iscyano, nitro, formyl, thiazolyl or (2-4C)alkanoyl, the alkylation,preferably in the presence of a suitable base as defined hereinbefore,of a compound of the formula V with a compound of the formula R² -Zwherein Z is a displaceable group as defined hereinbefore; providedthat, when there is an amino or hydroxy group in Ar¹ or on the phenylenegroup, any amino or hydroxy group may be protected by a conventionalprotecting group as defined hereinbefore or alternatively any such groupneed not be protected, whereafter any undesired protecting group in Ar¹or on the phenylene group is removed by conventional means.

The alkylation reaction is conveniently performed in a suitable inertsolvent as defined hereinbefore and at a temperature in the range, forexample, 10° to 150° C., conveniently at or near ambient temperature.

The starting materials of the formula V may be obtained by standardprocedures of organic chemistry as illustrated in the accompanyingExamples or by modifications thereto which are within the ordinary skillof an organic chemist.

(e) For the production of those compounds of the formula I wherein X¹ isa sulphinyl or sulphonyl group the oxidation of a compound of theformula I wherein X¹ is a thio group.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15° to 35° C. When a compound carrying a sulphinyl group isrequired a milder oxidising agent may also be used, for example sodiumor potassium metaperiodate, conveniently in a polar solvent such asacetic acid or ethanol. It will be appreciated that when a compound ofthe formula I containing a sulphonyl group is required, it may beobtained by oxidation of the corresponding sulphinyl compound as well asof the corresponding thio compound.

(f) For the production of those compounds of the formula I wherein Ar¹bears an alkyl substituent on an available nitrogen atom, or wherein thephenylene group bears an alkoxy substituent, the alkylation of acompound of the formula I wherein Ar¹ bears a hydrogen atom on saidavailable nitrogen atom, or wherein the phenylene group bears a hydroxysubstituent.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of an available nitrogen atom, or of hydroxy toalkoxy, for example an alkyl halide, for example a (1-4C)alkyl chloride,bromide or iodide, in the presence of a suitable base. A suitable basefor the alkylation reaction is, for example, an alkali or alkaline earthmetal carbonate, sodium hydroxide, potassium hydroxide, sodium hydrideor potassium hydride. The alkylation reaction is preferably performed ina suitable inert solvent or diluent, for example N,N-dimethylformamide,dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, andat a temperature in the range, for example, 10° to 150° C., convenientlyat or near ambient temperature.

(g) For the production of those compounds of the formula I wherein Ar¹bears one or more thioxo substituents, the reaction of a compound of theformula I wherein Ar¹ bears one or more oxo substituents with a thiationreagent such that each oxo substituent is converted into a thioxosubstituent; provided that, when there is an amino or hydroxy group inAr¹ or on the phenylene group, or when Q is amino, any such group may beprotected by a conventional protecting group or alternatively any suchgroup need not be protected, whereafter any undesired protecting groupin Ar¹, the phenylene group or Q is removed by conventional means.

A suitable thiation reagent is, for example, any agent known in the artfor the conversion of an oxo group to a thioxo group such as, forexample,2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide(Lawesson's Reagent) or phosphorus pentasulphide. The thiation reactionis generally carried out with the required stoichiometric amount ofthiation reagent in order to reduce the risk of damage to otherfunctional groups. In general the reaction is carried out in a suitablesolvent or diluent such as toluene, xylene or tetrahydrofuran and at atemperature, for example, at or near the reflux temperature of thesolvent or diluent, that is in the range 65° to 150° C.

When a pharmaceutically-acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with a suitable acid or base using a conventional procedure.When an optically active form of a compound of the formula I isrequired, it may be obtained by carrying out one of the aforesaidprocedures using an optically active starting material, or by resolutionof a racemic form of said compound using a conventional procedure.

As stated previously, the compounds of the formula I are inhibitors ofthe enzyme 5-LO. The effects of this inhibition may be demonstratedusing one or more of the standard procedures set out below:

a) An in vitro assay system involving incubating a test compound withheparinised human blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using specific radioimmunoassays describedby Carey and Forder (F. Carey and R. A. Forder, Prostaglandins,Leukotrienes Med., 1986, 22, 57; Prostaglandins, 198, 28, 666; Brit. J.Pharmacol. 1985, 84, 34P) which involve the use of a protein-LTB₄conjugate produced using the procedure of Young et alia (Prostaglandins,1983, 26(4), 605-613). The effects of a test compound on the enzymecyclooxygenase (which is involved in the alternative metabolic pathwayfor arachidonic acid and gives rise to prostaglandins, thromboxanes andrelated metabolites) may be measured at the same time using the specificradioimmunoassay for thromboxane B₂ (TxB₂) described by Carey and Forder(see above). This test provides an indication of the effects of a testcompound against 5-LO and also cyclooxygenase in the presence of bloodcells and proteins. It permits the selectivity of the inhibitory effecton 5-LO or cyclooxygenase to be assessed.

b) An ex vivo assay system, which is a variation of test a) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and TxB₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

c) An in vivo system involving measuring the effects of a test compoundadministered orally against the liberation of LTB₄ induced by zymosanwithin an air pouch generated within the subcutaneous tissue of the backof male rats. The rats are anaesthetised and air pouches are formed bythe injection of sterile air (20 ml). A further injection of air (10 ml)is similarly given after 3 days. At 6 days after the initial airinjection the test compound is administered (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to hydroxypropylmethylcellulose), followedby the intrapouch injection of zymosan (1 ml of a 1% suspension inphysiological saline). After 3 hours the rats are killed, the airpouches are lavaged with physiological saline, and the specificradioimmunoassay described above is used to assay LTB₄ in the washings.This test provides an indication of inhibitory effects against 5-LO inan inflammatory milieu.

Although the pharmacological properties of the compounds of the formulaI vary with structural changes as expected, in general compounds of theformula I possess 5-LO inhibitory effects at the followingconcentrations or doses in at least one of the above tests a)-c):

Test a): IC₅₀ (LTB₄) in the range, for example, 0.01-40 μM IC₅₀ (TxB₂)in the range, for example, 40-200 μM;

Test b): oral ED₅₀ (LTB₄) in the range, for example, 0.1-100 mg/kg;

Test c): oral ED₅₀ (LTB₄) in the range, for example, 0.1-100 mg/kg.

No overt toxicity or other untoward effects are present in tests b)and/or c) when compounds of the formula I are administered at severalmultiples of their minimum inhibitory dose or concentration.

Thus, by way of example, the compound ethyl2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrilehas an IC₅₀ of 0.5 μM against LTB₄ in test a); the compound2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrilehas an IC₅₀ of 0.08 μM in test a); the compound2,2-diallyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]acetonitrilehas an IC₅₀ of 0.05 μM in test a); and the compound3-ethyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pentan-2-onehas an IC₅₀ of 0.15 μM in test a). In general those compounds of theformula I which are particularly preferred have an IC₅₀ of <1 μM againstLTB₄ in test a).

These compounds are examples of compounds of the invention which showselective inhibitory properties for 5-LO as opposed to cyclooxygenase,which selective properties are expected to impart improved therapeuticproperties, for example, a reduction in or freedom from thegastrointestinal side-effects frequently associated with cyclooxygenaseinhibitors such as indomethacin.

According to a further feature of the invention there is provided apharmaceutical composition which comprises an α,α-dialkylbenzylderivative of the formula I, or a pharmaceutically-acceptable saltthereof, in association with a pharmaceutically-acceptable diluent orcarrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powderor a liquid aerosol; for sub-lingual or buccal use, for example a tabletor capsule; or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is an α,α-dialkylbenzyl derivativeof the formula I, or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided anα,α-dialkylbenzyl derivative of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the formula I are useful intreating those allergic and inflammatory conditions which are due aloneor in part to the effects of the metabolites of arachidonic acid arisingby the linear (5-LO catalysed) pathway and in particular theleukotrienes, the production of which is mediated by 5-LO. As previouslymentioned, such conditions include, for example, asthmatic conditions,allergic reactions, allergic thiniris, allergic shock, psoriasis, atopicdermatitis, cardiovascular and cerebrovascular disorders of aninflammatory nature, arthritic and inflammatory joint disease, andinflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lover doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, the compounds ofthe formula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylicacid, ibuprofen, sulindac, rolmerin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises anα,α-dialkylbenzyl derivative of the formula I, or apharmaceutically-acceptable salt thereof as defined hereinbefore, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent (such as those mentioned above), and apharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of the compounds of the formula I may bedemonstrated, for example in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I have satisfactory microanalysesand their structures were confirmed by NMR and mass spectral techniques;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points are uncorrected and were determined using a MerrierSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used: ##STR2##

EXAMPLE 1

A mixture of 2-ethyl-2-(3-hydroxyphenyl)butyronitrile (0.234 g),6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one (1.1 equivalents:European Patent Application No. 0385662, Example 6 thereof), potassiumcarbonate (0.5 g) and DMF (10 ml) was stirred at ambient temperature for68 hours. The mixture was partitioned between methylene chloride andwater. The organic layer was washed with water and with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 1:1 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrile(0.368 g, 78%), as an oil.

NMR Spectrum (CDCl₃, δ values) 0.90(t, 6H), 1.97(m, 4H), 3.74(s, 3H),5.14(s, 2H), 6.74(d, 1H), 6.92(m, 1H), 6.97(m, 1H), 7.05(t, 1H), 7.33(m,1H), 7.40(m, 1H), 7.65(m, 2H), 7.69(d, 1H).

The 2-ethyl-2-(3-hydroxyphenyl)butyronitrile used as a starting materialwas obtained as follows:

n-Butyl-lithium (1.6M in hexane, 18.8 ml) was added dropwise to asolution of di-isopropylamine (4.21 ml) in THF (100 ml) which had beencooled to -78° C. The mixture was stirred at -78° C. for 30 minutes. Asolution of 3-methoxyphenylacetonitrile (4.18 ml) in THF (10 ml) wasadded dropwise and the mixture was stirred and allowed to warm to 0° C.The mixture was stirred at 0° C. for 15 minutes then recooled to -78° C.A solution of ethyl iodide (2.64 ml) in THF (10 ml) was added and themixture was stirred for 16 hours and allowed to warm to ambienttemperature. The mixture was acidified to pH4 by the addition of diluteaqueous hydrochloric acid and partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a4:1 v/v mixture of hexane and ethyl acetate as eulent. There was thusobtained 2-(3-methoxyphenyl)butyronitrile (4.1 g, 78%) as an oil whichwas used without further purification.

A portion (0.875 g) of the product so obtained was alkylated with ethyliodide using an analogous procedure to that described immediately above.There was thus obtained 2-ethyl-2-(3-methoxyphenyl)butyronitrile (0.721g, 65%) as an oil.

A solution of a portion (0.609 g) of the product so obtained inmethylene chloride (10 ml) was cooled in an ice-bath and borontribromide (1M in methylene chloride, 6 ml) was added. The mixture wasstirred at ambient temperature for 16 hours. The mixture was partitionedbetween diethyl ether and water. The organic extracts were combined andextracted with 2N aqueous sodium hydroxide solution. The aqueous extractwas acidified with dilute aqueous hydrochloric acid and extracted withdiethyl ether. The organic phase was washed with brine, dried (MgSO₄)and evaporated. The residue was purified by column chromatography usinga 3:1 v/v mixture of hexane and ethyl acetate as eluent. There was thusobtained the required starting material (0.406 g, 72%) as an oil whichwas used without further purification.

EXAMPLE 2

The alkylation of 2-ethyl-2-(3-hydroxyphenyl)butyronitrile described inExample 1 was repeated except that 2-bromomethylnaphthalene was used inplace of 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one. There wasthus obtained 2-ethyl-2-[3-(naphth-2-ylmethoxy)phenyl]butyronitrile in96% yield, m.p. 108°-110° C.

EXAMPLE 3

In an analogous procedure to that described in Example 1,2-bromomethylnaphthalene was reacted with ethyl 3-hydroxybenzoate togive ethyl 3-(naphth-2-ylmethoxy)benzoate in 85% yield, m.p. 45°-46.5°C.

A solution of the product so obtained (1.53 g) in diethyl ether (15 ml)was added to ethylmagnesium iodide [prepared from ethyl iodide (2.34 g)and magnesium (0.42 g) in diethyl ether (30 ml)]. The mixture was heatedto reflux for 20 minutes. The mixture was cooled to ambient temperatureand water (3 ml) was added, The mixture was partitioned between ethylacetate and water. The organic phase was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of hexane and ethylacetate as eluent. There was thus obtained3-[3-(naphth-2-ylmethoxy)phenyl]pentan-3-ol (1.3 g, 81%) m.p. 60°-63° C.

Sodium hydride (50% w.w. dispersion in mineral oil; 0.05 g) was addedportionwise to a solution of a portion (0.25 g) of the propan-1-ol soobtained in DMF (5 ml) and the mixture was stirred at ambienttemperature for 10 minutes. Methyl iodide (0.1 ml) was added and themixture was stirred at ambient temperature for 50 hours. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using increasingly polar mixtures ofhexane and ethyl acetate as eluent. There was thus obtained methyl3-[3-(naphth-2-ylmethoxy)phenyl]pent-3-yl ether (0.09 g, 35%), m.p.70°-72° C. (recrystallised from hexane).

EXAMPLE 4

The alkylation of 2-ethyl-2-(3-hydroxyphenyl)butyronitrile as describedin Example 1 was repeated except that 2-chloromethylquinolinehydrochloride was used in place of6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one. There was thusobtained 2-ethyl-2-[3-(2-quinolylmethoxy)phenyl]butyronitrile in 69%yield, m.p. 66°-67° C.

NMR Spectrum (CDCl₃, δ values) 0.87(t, 6H), 1.94(m, 4H), 5.40(s, 2H),6.56(m, 1H), 7.01(m, 1H), 7.08(m, 1H), 7.30(t, 1H), 7.56(m, 1H), 7.69(d,1H), 7.75(m, 1H), 7.84(m, 1H), 8.08(m, 1H), 8.20(d, 1H).

EXAMPLE 5

The reaction described in Example 1 was repeated except that2-(3-hydroxyphenyl)-2-methylbutyronitrile was used in place of2-ethyl-2-(3-hydroxyphenyl)butyronitrile. There was thus obtained2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrilein 45% yield as a gum.

NMR Spectrum (CDCl₃, δ values) 0.96(t, 3H), 1.69(s, 3H), 1.95(m, 2H),3.73(s, 3H), 5.14(s, 2H), 6.74(d, 1H), 6.92(m, 1H), 7.03(m, 1H), 7.10(m,1H), 7.31(t, 1H), 7.40(d, 1H), 7.65(m, 2H), 7.69(d, 1H).

The 2-(3-hydroxyphenyl)-2-methylbutyronitrile used as a startingmaterial was obtained as follows:

The procedures described in the portion of Example 1 which is concernedwith the preparation of starting materials were repeated except that3-methoxyphenylacetonitrile was alkylated in turn with methyl iodide andethyl iodide. The 2-(3-methoxyphenyl)-2-methylbutyronitrile so obtainedwas treated with boron tribromide to give the required starting materialin an overall yield of 8% as a gum.

NMR Spectrum (CDCl₃, δ values) 0.97(t, 3H), 1.69(s, 3H), 1.95(m, 2H),5.11(s, 1H), 6.77(m, 1H), 6.94(m, 1H), 6.97(m, 1H), 7.25(t, 1H).

EXAMPLE 6

The reaction described in Example 1 was repeated except that2-allyl-2-(3-hydroxyphenyl)butyronitrile was used in place of2-ethyl-2-(3-hydroxyphenyl)butyronitrile. There were thus obtained2-allyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrilein 16% yield as a gum.

NMR Spectrum (CDCl₃, δ values) (0.91(t, 3H), 1.98(m, 2H), 2.65(d, 2H),3.73(s, 3H), 5.13(m, 1H), 5.14(s, 2H), 5.64(m, 1H), 6.73(d, 1H), 6.92(m,1H), 6.96(m, 1H), 7.05(m, 1H), 7.32(t, 1H), 7.40(d, 1H), 7.62(m, 2H),7.65(d, 1H).

The 2-allyl-2-(3-hydroxyphenyl)butyronitrile used as a starting materialwas obtained as follows:

The procedures described in the portion of Example 1 which is concernedwith the preparation of starting materials were repeated except that3-methoxyphenylacetonitrile was alkylated in turn with ethyl iodide andallyl bromide. The 2-allyl-2-(3-methoxyphenyl)butyronitrile so obtainedwas treated with boron tribromide to give the required starting materialin an overall yield of 46% as a gum.

NMR Spectrum (CDCl₃, δ values) 0.93(t, 3H), 1.99(m, 2H), 2.64(d, 2H),5.10(m, 1H), 5.17(m, 1H), 5.27(s, 1H), 5.66(m, 1H), 6.78(m, 1H), 6.93(m,1H), 6.94(m, 1H), 7.26(t, 1H).

EXAMPLE 7

The reaction described in Example 1 was repeated except that2,2-diallyl-2-(3-hydroxyphenyl)acetonitrile was used in place of2-ethyl-2-(3-hydroxyphenyl)butyronitrile. There was thus obtained2,2-diallyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]acetonitrilein 7% yield as a gum.

NMR Spectrum (CDCl₃, δ values) 2.68(m, 4H), 3.73(s, 3H), 5.09(s, 2H),5.14(s, 2H), 5.16(m, 2H), 5.64(m, 2H), 6.73(d, 1H), 6.92(m, 1H), 6.99(m,1H), 7.06(m, 1m), 7.31(t, 1H), 7.39(m, 1H), 7.55(m, 2H), 7.59(d, 1H).

The 2,2-diallyl-2-(3-hydroxyphenyl)acetonitrile used as a startingmaterial was obtained as follows:

The procedures described in the portion of Example 1 which is concernedwith the preparation of starting materials were repeated except that3-methoxyphenylacetonitrile was alkylated with allyl bromide. The2,2-diallyl-2-(3-methoxyphenyl)acetonitrile so obtained was treated withboron tribromide to give the required starting material in an overallyield of 39% as an oil.

NMR Spectrum (CDCl₃, δ values) 2.68(d, 4H), 5.11(m, 2H), 5.18(m, 2H),5.65(m, 2H), 6.78(m, 1H), 6.93(m, 1H), 6.94(m, 1H), 7.25(t, 1H).

EXAMPLE 8

The procedure described in the last paragraph of Example 3 was repeatedexcept that ethyl iodide was used in place of methyl iodide. There wasthus obtained ethyl 3-[3-(naphth-2-ylmethoxy)phenyl]pent-3-yl ether in51% yield, m.p. 45°-47° C.

EXAMPLE 9

Using an analogous procedure to that described in Example 1,6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with3-ethyl-3-(3-hydroxyphenyl)pentan-2-one to give3-ethyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pentan-2-onein 40% yield as a gum.

NMR Spectrum (CDCl₃, δ values) 0.67(t, 6H), 1.98(m, 4H), 3.73(s, 3H),5.10(s, 2H), 6.74(d, 1H), 6.83(m, 1H), 6.84(m, 1H), 6.88(m, 1H), 7.27(t,1H), 7.39(d, 1H), 7.63(m, 2H), 7.69(d, 1H).

The 3-ethyl-3-(3-hydroxyphenyl)pentan-2-one used as a starting materialwas obtained as follows:

An excess of oxalyl chloride was added dropwise to a stirred mixture of3-methoxyphenylacetic acid (33.2 g), DMF (4 ml) and methylene chloride(800 ml) and the mixture was stirred at ambient temperature for 65hours. The mixture was evaporated to leave 3-methoxyphenylacetylchloride (39.6 g).

Triethylamine (44.4 g) was added portionwise to a stirred mixture of3-methoxyphenylacetyl chloride (36.9 g), N,O-dimethylhydroxylaminehydrochloride (21.5 g) and methylene chloride (500 ml) which had beencooled to 0° C. The mixture was stirred at 5° C. for 90 minutes and atambient temperature for 65 hours. The mixture was washed in turn withdilute aqueous hydrochloric acid, a saturated aqueous sodium bicarbonatesolution and brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 1:1 v/v mixture of hexane andethyl acetate as eluent. There was thus obtainedN,O-dimethyl-3-methoxyphenylacetohydroxamic acid (29 g) as an oil.

Methylmagnesium iodide [prepared from magnesium (6.8 g) and methyliodide (39.8 g) in diethyl ether (200 ml)] was added to a stirredsolution of the hydroxamic acid so obtained in THF (500 ml) which hadbeen cooled to 5° C. The mixture was stirred at ambient temperature for65 hours. The mixture was partitioned between diethyl ether and asaturated aqueous ammonium chloride solution. The organic phase waswashed with brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 2:1 v/v mixture of hexane andethyl acetate as eluent. There was thus obtained1-(3-methoxyphenyl)propan-2-one (13.2 g) as an oil.

NMR Spectrum (CDCl₃, δ values) 2.14(s, 3H), 3.65(s, 2H), 3.80(s, 3H),6.80(m, 2H), 7.24(t, 1H).

Using analogous procedures to those described in the portion of Example1 which is concerned with the preparation of starting materials,1-(3-methoxyphenyl)propan-2-one was alkylated with ethyl iodide and the3-ethyl-3-(3-methoxyphenyl)pentan-2-one so obtained in 5% yield wastreated with boron tribromide to give3-ethyl-3-(3-hydroxyphenyl)pentan-2-one in 44% yield as an oil.

NMR Spectrum (CDCl₃, δ values) 0.68(t, 6H), 1.89(s, 3H), 1.98(m, 4H),5.28(m, 1H), 6.68(m, 1H), 6.75(m, 1H), 6.79(m, 1m), 7.22(t, 1H).

EXAMPLE 10

A solution of 1-[3-(naphth-2-ylmethoxy)phenyl]propan-2-one (1.45 g) inTHF (10 ml) was added dropwise to a stirred mixture of sodium hydride[50% w/w dispersion in mineral oil, 0.48 g; washed with petroleum ether(b.p. 40°-60° C.) to remove the mineral oil] in N-methylpyrrolidin-2-one(10 ml). The resultant mixture was stirred at ambient temperature for 30minutes. The mixture was cooled to 10° C. and a solution of allylbromide (1.21 g) in THF (5 ml) was added dropwise. The mixture wasstirred at ambient temperature for 1 hour. Water was added and themixture was acidified to pH 5 by the addition of dilute hydrochloricacid. The mixture was extracted with diethyl ether. The organic extractwas washed with water and with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 4:1 v/v mixture ofpetroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent.There was thus obtained 1,1-diallyl-1-[3-(naphth-2-ylmethoxy)phenyl]propan-2-one (1.5 g, 68%), m.p. 73°-74° C.

NMR Spectrum (CDCl₃, δ values) 1.86(s, 3H), 2.17(d, 4H), 4.8-5.7(m, 8H),6.65-8.0(m, 11H).

The 1-[3-(naphth-2-ylmethoxy)phenyl]propan-2-one used as a startingmaterial was obtained as follows:

A mixture of 2-bromomethylnaphthalene (19.5 g), 3-hydroxyphenylaceticacid (6.09 g), potassium carbonate (22 g) and acetone (100 ml) wasstirred and heated to reflux for 6 hours. The mixture was cooled,filtered and evaporated. A mixture of the residue, 2N sodium hydroxidesolution (125 ml) and ethanol (30 ml) was heated to reflux for 2 hours.The solution was cooled, washed with diethyl ether and acidified to pH4by the addition of concentrated aqueous hydrochloric acid. Theprecipitate was isolated and dried. There was thus obtained3-(naphth-2-ylmethoxy)phenylacetic acid in 94% yield, m.p. 142°-143° C.

Methyl-lithium (1.4M in diethyl ether, 35.7 ml) was added dropwise to astirred mixture of a portion (2.92 g) of the phenylacetic acid soobtained, lithium iodide (1.34 g) and diethyl ether (100 ml) and theresultant mixture was stirred at ambient temperature for 2 hours.Aniline (0.003 ml) was added and the mixture was partitioned betweendiethyl ether and a dilute aqueous hydrochloric acid solution. Theorganic phase was washed with water, with a saturated aqueous sodiumthiosulphate solution, with a saturated sodium bicarbonate solution andwith brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using methylene chloride as eluent. There was thusobtained the required starting material (1 g, 34%), m.p. 48°-49° C.

NMR Spectrum (CDCl₃, δ values) 2.1(s, 3H), 3.63(s, 2H), 5.2(s, 2H),6.4-8.0(m, 11H).

EXAMPLE 11

A solution of2-[1-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl)propyl]thiazole (0.754 g) inTHF (20 ml) was added to a stirred suspension of potassium hydride (35%w/w dispersion in mineral oil, 0.1 g) in THF (6 ml) and the mixture wasstirred at ambient temperature for 2 hours. Ethyl iodide (0.39 g) wasadded and the mixture was stirred at ambient temperature for 16 hours.The mixture was partitioned between ethyl acetate and a saturatedaqueous ammonium chloride solution. The organic phase was washed withbrine, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:1 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained2-[3-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl)pent-3-yl]thiazole (0.255 g,31%), m.p. 81°-82° C.

NMR Spectrum (CDCl₃, δ values) 0.73(t, 6H), 2.27(m, 4H), 5.16(s, 2H),6.6(m, 2H), 6.72(m, 1H), 7.18(d, 1H), 7.5(m, 1H), 7.66(d, 1H), 7.85(m,4H).

The 2-[1-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl)propyl]thiazole used asa starting material was obtained as follows:

Sodium hydride (60% w/v dispersion in mineral oil, 4.64 g) was addedportionwise to a stirred solution of 2-naphthalenemethanol (18.35 g) inN,N-dimethylacetamide (400 ml) and the mixture was stirred at ambienttemperature for 45 minutes. A solution of 3,5-difluorobenzonitrile (16.1g) in N,N-dimethylacetamide (100 ml) was added and the mixture wasstirred at ambient temperature for 66 hours. The mixture was evaporatedand the residue was partitioned between methylene chloride and water.The organic phase was washed with brine, dried (MgSO₄) and evaporated.The residue was crystallised under ethanol. There was thus obtained5-fluoro-3-(naphth-2-ylmethoxy)benzonitrile (23.5 g), m.p. 92°-93° C.

A solution of 2-bromothiazole (2.33 ml) in diethyl ether (25 ml) wasadded to a stirred mixture of n-butyl-lithium (1.6M in hexane, 16.13 ml)and diethyl ether (10 ml) which had been cooled to -75° C. The mixturewas stirred at -75° C. for 75 minutes. A solution of5-fluoro-3-(naphth-2-ylmethoxy)benzonitrile (7.18 g) in THF (25 ml) wasadded and the mixture was stirred at -75° C. for 30 minutes. A saturatedsolution of hydrogen chloride in diethyl ether was added and theacidified mixture was allowed to warm to ambient temperature. Themixture was partitioned between methylene chloride and water. Theorganic phase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was recrystallised from ethanol. There was thusobtained 5-fluoro-3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone (7.17g), 118°-119° C.

NMR Spectrum (CDCl₃, δ values) 5.31(s, 2H), 7.01(m, 1H), 7.5(m, 2H),7.56(m, 1H), 7.73(d, 1H), 7.9(m, 5H), 8.01(t, 1H), 8.06(d, 1H).

A mixture of a portion (2.72 g) of the compound so obtained,ethyltriphenylphosphonium bromide (2.78 g), potassium carbonate (2.59 g)and 1,4-dioxan (50 ml) was stirred and heated to reflux for 5 days. Themixture was cooled to ambient temperature and partitioned between ethylacetate and water. The organic phase was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:1 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained5-fluoro-3-(naphth-2-ylmethoxy)-β-methyl-α-(2-thiazolyl)styrene (1.2 g),as a mixture of (E)- and (Z)-isomers.

After appropriate repetition of the above-described reactions, a mixtureof the isomers (27.77 g), 30% palladium-on-charcoal catalyst (9.29 g)and ethanol (200 ml) was stirred under an atmosphere of hydrogen for 2days. A further portion of catalyst (9.29 g) was added and the reactionwas continued for a second period of 2 days. A further portion ofcatalyst (9.29 g) was added and the reaction was continued for a further2 days. The mixture was filtered and the filtrate was evaporated. Theresidue was partitioned between methylene chloride and a saturatedaqueous sodium bicarbonate solution. The aqueous phase was acidified bythe addition of concentrated aqeuous hydrochloric acid and extractedwith methylene chloride. The organic solutions were combined, washedwith brine, dried (MgSO₄) and evaporated. There was thus obtained2-[1-(5-fluoro-3-hydroxyphenyl)propyl]thiazole (6.61 g), m.p. 86°-89° C.

A mixture of a portion (2.37 g) of the thiazole so obtained,2-bromomethylnaphthalene (2.21 g), potassium carbonate (4 g) and DMF(100 ml) was stirred at ambient temperature for 18 hours. The mixturewas evaporated and the residue was partitioned between methylenechloride and water. The organic phase was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:1 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained2-[1-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl)propyl]thiazole (3.15 g) asa gum.

NMR Spectrum (CDCl₃, δ values) 0.92(t, 3H), 2.08(m, 1H), 2.31(m, 1H),4.14(t, 1H), 5.18(s, 2H), 6.62(m, 1H), 6.67(m, 1H), 6.80(t, 1H), 7.16(d,1H), 7.50(m, 3H), 7.68(d, 1H), 7.85(m, 4H).

EXAMPLE 12

A mixture of 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one (0.296 g),2-[3-(3-tert-butyldimethylsilyloxy-5-fluorophenyl)pent-3-yl]thiazole(0.447 g), potassium fluoride (0.136 g) and DMF (10 ml) was stirred atambient temperature for 16 hours. The mixture was evaporated and theresidue was partitioned between methylene chloride and water. Theorganic phase was washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 2:1 v/v mixture ofhexane and ethyl acetate as eluent. There was thus obtained2-[3-(5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl)pent-3-yl]thiazole(0.102 g) as a gum.

NMR Spectrum (CDCl₃, δ values) 0.75(t, 6H), 2.28(m, 4H), 3.73(s, 3H),5.05(s, 2H), 6.55(m, 1H), 6.63(m, 1H), 6.69(m, 1H), 6.74(d, 1m), 7.22(d,1H), 7.37(d, 1H).

The 2-[3-(3-tert-butyldimethylsilyloxy-5-fluorophenyl)pent-3-yl]thiazoleused as a starting material was obtained as follows:

A mixture of 2-[1-(5-fluoro-3-hydroxyphenyl)propyl]thiazole (2.37 g)tert-butyldimethylsilyl chloride (1.57 g) imidazole (0.75 g) and DMF(100 ml) was stirred at ambient temperature for 17 hours. The mixturewas evaporated and the residue was partitioned between methylenechloride and water. The organic phase was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:1 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained2-[1-(3-tert-butyldimethylsilyloxy-5-fluorophenyl)propyl]thiazole (2.16g) as an oil.

A portion (1.06 g) of the compound so obtained was reacted with ethyliodide using an analogous procedure to that described in Example 11.There was thus obtained2-[3-(3-tert-butyldimethylsilyloxy-5-fluorophenyl)pent-3-yl]thiazole(0.454 g) as an oil.

NMR Spectrum (CDCl₃, δ values) 0.15(m, 6H), 0.76(t, 6H), 0.95(m, 9H),2.28(m, 4H), 6.41(m, 1H), 6.52(m, 1H), 6.63(m, 1H), 7.25(d, 1H), 7.71(d,1H).

EXAMPLE 13

The reaction described in Example 1 was repeated except that2-benzyl-2-(3-hydroxyphenyl)butyronitrile was used in place of2-ethyl-2-(3-hydroxphenyl)butyronitrile. There was thus obtained2-benzyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrilein 33% yield as a glass.

NMR Spectrum (CDCl₃, δ values) 0.93(t, 3H), 2.08(q, 2H), 3.15(q, 2H),3.73(s, 3H), 5.07(s, 2H), 6.74(d, 1H), 6.95(m, 5H), 7.18(m, 3H), 7.25(m,1H), 7.35(m, 1H), 7.63(m, 2H), 7.69(d, 1H).

The 2-benzyl-2-(3-hydroxyphenyl)butyronitrile used as a startingmaterial was obtained as follows:

The procedures described in the portion of Example 1 which is concernedwith the preparation of starting materials were repeated except that3-methoxyphenylacetonitrile was alkylated in turn with ethyl iodide andbenzyl bromide. The 2-benzyl-2-(3-methoxyphenyl)butyronitrile soobtained was treated with boron tribromide to give the required startingmaterial in an overall yield of 20% as a gum.

NMR Spectrum (CDCl₃, δ values) 0.94(t, 3H), 2.08(q, 2H), 3.14(q, 2H),5.35(broad hump, 1H), 6.90(m, 4H), 7.20(m, 5H). ##STR3##

We claim:
 1. An α,α-dialkylbenzyl derivative of the formula Iwherein Ar¹is a 10-membered bicyclic heterocyclic moiety containing one or twonitrogen heteroatoms in one ring and optionally containing a furthernitrogen heteroatom in the second ring, and Ar¹ may optionally bear upto four substituents selected from halogeno, hydroxy, cyano, oxo,thioxo, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl, phenyl, benzoyl,phenyl-(1-4C)alkyl, α,α-difluorobenzyl, α-hydroxybenzyl andα-[(1-4C)alkoxy]benzyl and wherein said phenyl substituent or any ofsaid substituents which contain a phenyl group may optionally bear asubstituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; A¹ isa direct link to X¹ or is (1-3C)alkylene; X¹ is oxy, thio, sulphinyl orsulphonyl; the phenylene group may optionally bear one or twosubstituents R³ selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, ureido, (1-4C)alkyl, (1-4C)alkoxy and fluoro-(1-4C)alkyl;each of R¹ and R², which may be the same or different is (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl, fluoro-(1-4C)alkyl, phenyl orphenyl-(1-4C)alkyl and wherein said phenyl or phenyl-(1-4C)alkyl groupmay optionally bear one or two substituents selected from halogeno,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, provided that both of R¹and R² are not methyl or fluoromethyl; and Q is cyano, amino, nitro,formyl, (1-4C)alkoxy, thiazolyl or (2-4C)alkanoyl; or apharmaceutically-acceptable salt thereof.
 2. An α,α-dialkylbenzylderivative of the formula I as claimed in claim 1 wherein Ar¹ is2-quinolyl, 6-quinolyl, 6-quinoxazinyl, 2-oxo-1,2-dihydroquinolin-3-yl,2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl,3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, which may optionally bearone, two or three substituents selected from fluoro, chloro, methyl,ethyl, 2-fluoroethyl, phenyl and benzyl;A¹ is a direct link to X¹, or ismethylene; X¹ is oxy, thio, sulphinyl or sulphonyl; the phenylene groupis 1,3-phenylene which may optionally bear one substituent R³ selectedfrom fluoro, chloro and trifluoromethyl; each of R¹ and R², which may bethe same or different, is methyl ethyl, propyl, allyl or benzyl,provided that both of R¹ and R² are not methyl; and Q is cyano, methoxy,ethoxy, 2-thiazolyl, acetyl or propionyl; or apharmaceutically-acceptable salt thereof.
 3. An α,α-dialkylbenzylderivative of the formula I as claimed in claim 1 wherein Ar¹ is2-quinolyl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;A¹ is methyleneand X¹ is oxy; the phenylene group bearing R³ is 1,3-phenylene or5-fluoro-1,3-phenylene; R¹ is ethyl or allyl; R² is methyl, ethyl, allylor benzyl; and Q is cyano or acetyl; or a pharmaceutically-acceptablesalt thereof.
 4. A specific compound of the formula I, or apharmaceutically-acceptable salt thereof as claimed in claim 1 selectedfrom:ylmethoxy)phenyl]butyronitrile,2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrile,2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyronitrile,2,2-diallyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]acetonitrileand3-ethyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pentan-2-one.5. A process for the preparation of an α,α-dialkylbenzyl derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof, as claimedin claim 1 which comprises:(a) the coupling of a compound of the formulaAr¹ -A¹ -X¹ -H with a compound of the formula II ##STR4## wherein Z is adisplaceable group; provided that, when there is an amino or hydroxygroup in Ar¹ or on the phenylene group, or when Q is amino, any amino orhydroxy group may be protected by a conventional protecting group oralternatively any such group need not be protected, whereafter anyundesired protecting group in Ar¹, the phenylene group or Q is removedby conventional means; (b) the coupling of a compound of the formula Ar¹-A¹ -X¹ -Z wherein Z is a displaceable group, or alternatively, when X¹is a thio group, Z may be a group of the formula Ar¹ -A¹ -X¹ -, with anorganometallic reagent of the formula III ##STR5## wherein M is analkali metal or an alkaline earth metal such as lithium or calcium or Mrepresents the magnesium halide portion of a conventional Grignardreagent; provided that, when there is an amino or hydroxy group in Ar¹or on the phenylene group, or when Q is amino, any amino or hydroxygroup may be protected by a conventional protecting group oralternatively any such group need not be protected, whereafter anyundesired protecting group in Ar¹, the phenylene group or Q is removedby conventional means; or (c) the coupling of a compound of the formulaIV ##STR6## with a compound of the formula Ar¹ -A¹ -Z wherein Z is adisplaceable group; provided that, when there is an amino or hydroxygroup in Ar¹ or on the phenylene group, or when Q is amino, any amino orhydroxy group may be protected by a conventional protecting group oralternatively any such group need not be protected, whereafter anyundesired protecting group in Ar¹, the phenylene group or Q is removedby conventional means; and (d) for the production of those compounds ofthe formula I wherein Q is cyano, nitro, formyl, thiazolyl or(2-4C)alkanoyl, the alkylation of a compound of the formula V ##STR7##with a compound of the formula R² -Z wherein Z is a displaceable group;provided that, when there is an amino or hydroxy group in Ar¹ or on thephenylene group, any amino or hydroxy group may be protected by aconventional protecting group or alternatively any such group need notbe protected, whereafter any undesired protecting group in Ar¹ or on thephenylene group is removed by conventional means; (e) for the productionof those compounds of the formula I wherein X¹ is a sulphinyl orsulphonyl group the oxidation of a compound of the formula I wherein X¹is a thio group; (f) for the production of those compounds of theformula I wherein Ar¹ bears an alkyl substituent on an availablenitrogen atom, or wherein the phenylene group bears an alkoxysubstituent, the alkylation of a compound of the formula I wherein Ar¹bears a hydrogen atom on said available nitrogen atom, or wherein thephenylene group bears a hydroxy substituent; (g) for the production ofthose compounds of the formula I wherein Ar¹ bears one or more thioxosubstituents, the reaction of a compound of the formula I wherein Ar¹bears one or more oxo substituents with a thiation reagent such thateach oxo substituent is converted into a thioxo substituent; providedthat, when there is an amino or hydroxy group in Ar¹ or on the phenylenegroup, or when Q is amino, any such group may be protected by aconventional protecting group or alternatively any such group need notbe protected, whereafter any undesired protecting group in Ar¹, thephenylene group or Q is removed by conventional means; and when apharmaceutically-acceptable salt of a compound of the formula I isrequired, it may be obtained by reaction of said compound with asuitable acid or base using a conventional procedure; and when anoptically active form of a compound of the formula I is required, it maybe obtained by carrying out one of the aforesaid procedures using anoptically active starting material, or by resolution of a racemic formof said compound using a conventional procedure.
 6. A pharmaceuticalcomposition which comprises an α,α-dialkylbenzyl derivative of theformula I, or a pharmaceutically-acceptable salt thereof, as claimed inany one of claims 1 and 3-6 in association with apharmaceutically-acceptable diluent or carrier.
 7. A method of treatinga disease or medical condition mediated alone or in part by one or moreleukotrienes which comprises administering to a warm-blooded animalrequiring such treatment an effective amount of an α,α-dialkylbenzylderivative of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in any one of claims 1 and 3-6.